Ischemic heart disease occurs when the heart muscle does not receive an adequate blood supply and is thus deprived of necessary levels of oxygen and nutrients. Ischemia is commonly a result of atherosclerosis which causes blockages in the coronary arteries that provide blood flow to the heart muscle.
Ischemic heart disease can result in certain adaptive responses within the heart which are likely to be beneficial. Among these responses are: 1) increased expression of angiogenic growth factors and their receptors, leading to the formation of collateral circulation around blocked coronary arteries; 2) increased expression of glycolytic enzymes as a means to activate a metabolic pathway which does not require O2; and 3) expression of heat shock proteins which can protect the ischemic tissue from death.
At least some of these responses appear to be regulated by a complex oxygen sensing mechanism which eventually leads to the activation of transcription factors which control the expression of critical genes involved in this adaptation. Because this altered gene expression occurs only in response to hypoxia, which usually only occurs when a strain such as exercise is placed upon the diseased heart, cardiac patients do not usually receive much benefit from this endogenous compensatory mechanism. As a result, a number of conventional therapies attempt to supplement the natural therapeutic responses of the heart to ischemia.
For example, such treatments include pharmacological therapies, coronary artery bypass surgery and percutaneous revascularization using techniques such as balloon angioplasty. Standard pharmacological therapy is predicated on strategies that involve either increasing blood supply to the heart muscle or decreasing the demand of the heart muscle for oxygen and nutrients.
Increased blood supply to the myocardium is achieved by agents such as calcium channel blockers or nitroglycerin. These agents are thought to increase the diameter of diseased arteries by causing relaxation of the smooth muscle in the arterial walls. Decreased demand of the heart muscle for oxygen and nutrients is accomplished either by agents that decrease the hemodynamic load on the heart, such as arterial vasodilators, or those that decrease the contractile response of the heart to a given hemodynamic load, such as beta-adrenergic receptor antagonists.
Surgical treatment of ischemic heart disease is based on the bypass of diseased arterial segments with strategically placed bypass grafts (usually saphenous vein or internal mammary artery grafts). Percutaneous revascularization is based on the use of catheters to reduce the narrowing in diseased coronary arteries. All of these strategies are used to decrease the number of, or to eradicate ischemic episodes, but all have various limitations.
More recently, delivery of angiogenic factors or heat shock proteins via protein or gene therapy has been proposed to further augment the heart's natural response to ischemia. Indeed, various publications have discussed the uses of gene transfer for the treatment or prevention heart disease. See, for example, Mazur et al., “Coronary Restenosis and Gene Therapy”, Molecular and Cellular Pharmacology 21:104–111 (1994); French, B. A. “Gene Transfer and Cardiovascular Disorders” Herz. 18(4):222–229 (1993); Williams, “Prospects for Gene Therapy of Ischemic Heart Disease”, Am. J. Med. Sci. 306:129–136 (1993); Schneider and French “The Advent of Adenovirus: Gene Therapy for Cardiovascular Disease” Circulation 88:1937–42 (1993). International Patent Application No. PCT/US93/11133, entitled “Adenovirus-Mediated Gene Transfer to Cardiac and Vascular Smooth Muscle” reporting the use of adenovirus-mediated gene transfer for regulating function in cardiac vascular smooth muscle.
Accordingly, there exists a need in the art for compositions and methods for inducing the expression of beneficial hypoxia-inducible genes in ischemia-associated cells. Additionally, there exists a need for new vector compositions that allow efficient expression of a range of potentially beneficial genes that are activated by the sustained direct expression of a biologically active mammalian transcription factor. The present invention satisfies these needs and provides related advantages as well.